toxiclipasyn
Understanding the balance between functional and deleterious interactions of alpha-synuclein with lipid bilayers
Total Cost €
0EC-Contrib. €
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Project "toxiclipasyn" data sheet
The following table provides information about the project.
| Coordinator |
DEUTSCHES ZENTRUM FUR NEURODEGENERATIVE ERKRANKUNGEN EV
Organization address contact info |
| Coordinator Country | Germany [DE] |
| Project website | https://www.dzne.de/en/research/research-areas/fundamental-research/research-groups/di-monte/research-areasfocus/ |
| Total cost | 171˙460 € |
| EC max contribution | 171˙460 € (100%) |
| Programme |
1. H2020-EU.1.3.2. (Nurturing excellence by means of cross-border and cross-sector mobility) |
| Code Call | H2020-MSCA-IF-2015 |
| Funding Scheme | MSCA-IF-EF-ST |
| Starting year | 2017 |
| Duration (year-month-day) | from 2017-05-01 to 2019-04-30 |
Partnership
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| # | ||||
|---|---|---|---|---|
| 1 | DEUTSCHES ZENTRUM FUR NEURODEGENERATIVE ERKRANKUNGEN EV | DE (BONN) | coordinator | 171˙460.00 |
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Project objective
Proteins are among the most essential molecules of life. In order to fulfil their native function(s) they need to adopt a well-defined three-dimensional structure. However, under some circumstances, proteins can misfold and/or form toxic amyloid structures, which are the hallmark of a range of diseases including type 2 diabetes and neurodegenerative diseases. In particular, the small pre-synaptic protein, alpha-synuclein (AS), whose aggregation is the hallmark of Parkinson’s disease, can adopt in vivo and in vitro an intrinsically disordered conformation in solution and an alpha helical state when bound to membranes; the equilibrium between these two conformations has been shown to be important for its proposed native function, e.g. synaptic plasticity, and to modulate its kinetics of fibril formation. Here, I propose to investigate the physiological factors responsible for the switch between functional and deleterious interactions between membrane bilayers and AS due to ageing or disease using an innovative combination of biological, structural, thermodynamic and kinetic studies. In particular, I propose to use both synthetic lipid model systems and isolated synaptic vesicles to study the effect of ageing and the presence of lipids associated with Parkinson’s disease pathology on the nature of the interaction between AS and lipid bilayers. The synaptic vesicles will be isolated from the brain of mice at different ageing stages, as well as from mice carrying gene modifications or knock out related to PD. The interaction between AS and the vesicles will be studied using a range of biophysical techniques including circular dichroism, fluorescence and nuclear magnetic resonance spectroscopy, Atomic Force and Electron Microscopy. The aim of this study is to establish a thorough understanding of the interplay between changes in lipid composition and increased propensity of protein aggregation.
Publications
| year | authors and title | journal | last update |
|---|---|---|---|
| 2018 |
James W. P. Brown, Georg Meisl, Tuomas P. J. Knowles, Alexander K. Buell, Christopher M. Dobson, Céline Galvagnion Kinetic barriers to α-synuclein protofilament formation and conversion into mature fibrils published pages: 7854-7857, ISSN: 1359-7345, DOI: 10.1039/c8cc03002b |
Chemical Communications 54/56 | 2019-09-25 |
| 2018 |
Ingrid M. van der Wateren, Tuomas P. J. Knowles, Alexander K. Buell, Christopher M. Dobson, Céline Galvagnion C-terminal truncation of α-synuclein promotes amyloid fibril amplification at physiological pH published pages: 5506-5516, ISSN: 2041-6520, DOI: 10.1039/c8sc01109e |
Chemical Science 9/25 | 2019-09-25 |
| 2018 |
Michele Perni, Patrick Flagmeier, Ryan Limbocker, Roberta Cascella, Francesco A. Aprile, Céline Galvagnion, Gabriella T. Heller, Georg Meisl, Serene W. Chen, Janet R. Kumita, Pavan K. Challa, Julius B. Kirkegaard, Samuel I. A. Cohen, Benedetta Mannini, Denise Barbut, Ellen A. A. Nollen, Cristina Cecchi, Nunilo Cremades, Tuomas P. J. Knowles, Fabrizio Chiti, Michael Zasloff, Michele Vendruscolo, Christopher M. Dobson Multistep Inhibition of α-Synuclein Aggregation and Toxicity in Vitro and in Vivo by Trodusquemine published pages: 2308-2319, ISSN: 1554-8929, DOI: 10.1021/acschembio.8b00466 |
ACS Chemical Biology 13/8 | 2019-09-25 |
| 2018 |
Johnny Habchi, Sean Chia, Céline Galvagnion, Thomas C. T. Michaels, Mathias M. J. Bellaiche, Francesco Simone Ruggeri, Michele Sanguanini, Ilaria Idini, Janet R. Kumita, Emma Sparr, Sara Linse, Christopher M. Dobson, Tuomas P. J. Knowles, Michele Vendruscolo Cholesterol catalyses Aβ42 aggregation through a heterogeneous nucleation pathway in the presence of lipid membranes published pages: 673-683, ISSN: 1755-4330, DOI: 10.1038/s41557-018-0031-x |
Nature Chemistry 10/6 | 2019-09-25 |
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